CHRONIC KIDNEY DISEASE

CKD

Note - My diagram refers to the estimated GFR (eGFR), which is calculated solely off of the Creatinine (plus demographic variables like weight, gender, race, etc). While very helpful in chronic settings, it’s not very helpful in acute problems (because the kidney problem is still rapidly evolving). While the eGFR, Cr and BUN will definitely be abnormal in Acute Kidney Injury (AKI), the degree of elevation (of Cr and BUN) or depression (of eGFR) isn’t very informative.

Chronic Kidney Disease is quite common. Although it isn’t very symptomatic, there are a lot of nasty long-term complications (anemia, bone loss, cardiovascular damage). CKD is usually a result of poorly controlled HTN and diabetes. If patients don’t correct their blood pressure or blood glucose, then their kidneys will invariably fail, at which point it becomes End-Stage Renal Disease. Patients with CKD are vulnerable because they don’t have much GFR to spare. Avoid drugs that worsen GFR (Diuretics, ACEi, NSAIDs). The kidneys are shrunken.

End-Stage Renal Disease, aka Kidney Failure, is defined as a GFR less than 15. It may result from any kind of kidney injury (glomerular, tubular, inflammatory or vascular) that goes untreated. The most common causes (by far) are diabetes, HTN and glomerular diseases. Interestingly, the kidneys are very shrunken. The only cure is a transplant. But there aren’t enough donor kidneys, so most patients go on long-term dialysis, which they will stay on until the day that they die (or get that lucky transplant). When you put a shrunken kidney on dialysis, it will develop cysts. Dialysis ↑ risk of renal cell carcinoma. From personal experience, ESRD was the 2nd sickest population I encountered in the ER (#1 belongs to untreated AIDS).

Azotemia refers to elevated creatinine and BUN. Uremia is a term that refers to symptomatic azotemia. Uremia only begins once ~90% of renal function is lost. Uremia is usually quite vague, and requires laboratory confirmation. Symptoms include oliguria/anuria, anorexia, nausea, fatigue, malaise, platelet dysfunction (bleeding), pericarditis, asterixis and encephalopathy. A particularly interesting symptom is full-body itching without a rash.

DIALYSIS

Mechanical kidneys

Dialysis Machines are artificial kidneys. These are large (and expensive) machines. They allow patients to artificially urinate. Fluid is taken from the body, “pee” is filtered out, then clean fluid is returned. It’s similar to cardiopulmonary bypass, except for peepee. There are three kinds of dialysis.

Hemodialysis - this is the most common kind of dialysis. Must be performed in a dialysis center (or hospital). Each session takes half a day. Requires 3 sessions per week. Needles are inserted into a “shunt” on the patient’s arm, and their blood is filtered.

Peritoneal Dialysis - this machine is much cheaper, because it cleverly uses peritoneal fluid instead of blood, and peritoneal fluid requires a lot less filtration. Needles are inserted into the belly. The upside is that the machine can be brought home and run overnight. Only responsible patients are allowed to use it, since peritoneal infections are bad. Also, and this isn’t in textbooks, ESRD patients are notoriously irresponsible. After all, most of them got to this point by being non-adherent with their diabetic or HTN treatment. That’s an overgeneralization, though there’s some truth behind it.

Hemofiltration - reserved for really sick patients. They’re labwork is changing so fast that the usual “3 sessions per week” schedule ain’t sufficient. Instead, their blood is constantly filtered at a slow pace. The slow pace allows for sophisticated maneuvering by the nephrologist.

Vascular Access - it makes a big difference where you put the needle. The size of the vein determines the speed of the dialysis session. A big vein means a quick session.

Central Line - in an emergency, nephrologists can use a central line (subclavian, femoral or jugular vein) each time they dialyze someone. But central lines have a 1% complication rate (infection, clotting, restenosis). Instead, ESRD patients deserve a more permanent solution….

Fistula (Shunt) - surgically creating an AV fistula may seem dumb, but it dramatically improves vascular access for those undergoing routine dialysis. Shunts are just durable! They’re almost always placed in the arm. A surgeon fuses an artery and vein together. A few months later, the shunt is ready. The resultant fistula is really easy to stick with a needle, and has really low complication rates. On the physical exam, you can auscultate the shunt to investigate its patency. Open shunts make a “thrill” or whoosh sound.

Indications for Dialysis in patients with stage 5 CKD

Acidotic

Electrolyte abnormalities (especially hyperkalemia)

Intoxication of dialyzable drug (ASA, Lithium, Ethylene Glycol, Iso Alcohol, Mg Laxatives)

Overload of fluid (they’re swollen)

Uremic symptoms (too uncomfortable)

ACUTE KIDNEY INJURY

Fast azotemia

AKI is the fast onset of kidney damage. The kidney is probably our most fragile organ, but thankfully damage due to AKI is usually reversible. The chief symptom is oliguria, in addition to vague findings like fatigue and malaise. AKI is determined solely by labwork - there will be a sudden elevation in the Creatinine and BUN. This labwork pattern is called azotemia. Both the Cr and BUN will be elevated in AKI, but the ratio of Cr to BUN can tell you a lot. Namely, where is the “lesion” located.

Creatinine is inert. It’s not reabsorbed or secreted.

BUN is active. It can be reabsorbed or secreted, based on its surroundings. Reabsorption increases when the Diffusion Gradient is high (Prerenal) or the Hydrostatic Pressure is high (early Postrenal). Reabsorption decreases when the cells responsible for reabsorption die (Renal or late Postrenal).

Next let's look at the different kinds of AKI.

Pre-Renal AKI means that not enough blood reaches the kidney.

Intra-Renal AKI means that the nephron cells are directly injured.

Post-Renal AKI means that an obstruction is blocking the urine’s exit from the body.

PRE-RENAL AKI

Hypoperfusion

Pre-Renal AKI is due to poor circulation to the kidney. Usually dehydration or shock.

If there’s less blood flow, then inherently there is going to be less filtration occurring across the glomerulus -- hence the low GFR. And if filtration is decreased at the beginning of the nephron, then obviously the output of urine at the end of the nephron will be low (oliguria).

As fluid flows through the nephron, it’s important to know how the BUN and Cr behave. BUN can be resorbed, but Cr cannot. That’s why the serum BUN rises more than the serum Cr. In a healthy person, the ratio is usually 15:1. But in Prerenal AKF, the starving nephrons pull the RAAS alarm, which leads to increased reabsorption of water (and BUN) in the distal nephron. So patients with Prerenal AKF have their serum BUN levels “supercharged” without any modification of the Cr. BUN:Cr > 15. A few other lab tests, like FENa and Urine Osmolality will be normal, since those tests evaluate tubular function.

If hypoperfusion goes on long enough, eventually the nephron cells will die. At that point, we call it Acute Tubular Necrosis, which is a type of Intra-Renal AKI. A bit confusing, I know. But in my experience, test questions are usually abundantly clear here.

*Side note - Tacrolimus is a nephrotoxic cancer drug. Unlike most nephrotoxic drugs, its mechanism is pre-renal.

POST-RENAL AKI

Obstruction

Post-Renal AKI is due to blocked urine. It’s usually due to kidney stones, tumors or a big prostate. The pressure builds up in the kidney (hydronephrosis) and its tubules. That pressure limits the GFR. And that causes Azotemia.

Early on, the BUN:Cr ratio will be high (over 20), because the tubules haven’t died yet. Later, the high pressure eventually kills the renal tubular cells. That results in little-to-no BUN resorption (similar to Intra-Renal AKI), and the BUN:Cr ratio falls below 15. And now that the tubular cells are dead, the FENa rises over 2%, and the urine becomes diluted (failure to concentrate).

Here’s a tidbit about the prostate. The urine flows through the center of the prostate. In prostate cancer, the tumor usually grows on the periphery of the prostate, leaving urine flow untouched. But in benign prostate hypertrophy (BPH), the prostate growth is uniform, which squishes the flow of urine.

Kidney stones usually don’t cause post-renal AKI in a healthy person because the unaffected kidney can compensate for it. But in people with only one kidney, a stone can cause AKI.

ACUTE TUBULAR NECROSIS

Intrinsic

Acute Tubular Necrosis is when the nephron dies. The nephron cells slough off into the tube and congeal into plugs. The plugs block the flow of ultrafiltrate, creating problems upstream (GFR falls) and downstream (Oliguria). A few plugs will be eventually peed out -- which look like muddy brown granular casts.

There are discrete clinical phases in ATN. The first phase is the shortest and least meaningful. It is due to the ongoing ischemia of the nephron. Symptoms and lab abnormalities are relatively quiet. The second phase is the longest and most clinically apparent. Plugs form during this time period, which impacts the GFR. Thanks to the low GFR, all sorts of lab abnormalities occur (see diagram). This lasts a few weeks. Patients require admission during this period for electrolyte monitoring. Hyperkalemia is the biggest concern, because it can stop your heart. If the electrolytes are crashing faster than the doctors can correct them, then the patient must be put on temporary dialysis. The third phase is the recovery phase. Thankfully, tubular epithelial cells are capable of regeneration. This means that ATN is reversible! It takes the cells a few weeks to recover. But once they do recover, the new nephron cells aren’t properly calibrated. They produce too much urine (polyuria) and excrete too much potassium (hypokalemia).

On histology, you can see evidence of both ischemia and infarction. Infarcted cells are dead. They form plugs (pink blobs lacking nuclei) inside the tubes. Ischemic cells are in the process of dying. You can see them detaching from the BM (slivers of empty white space on the basilar side of the tubular cells). Note that the necrosis is not diffuse -- it’s patchy.

There are two causes of ATN.

Ischemic ATN is usually caused by shock. Seems simple enough. But the nephron has a peculiar quality that makes it especially vulnerable to ischemia. Nephron ischemia leads to vasoconstriction. Weird right? Shouldn’t the opposite be true? You should want vasodilation, to overcome the poor blood flow.

Why does vasoconstriction happens?

This is a conscious decision by the kidney. It doesn’t want to continue using underperfused nephrons. The NaK pumps move from the blood-side to the urine-side. They pump Na+ into the pee. That Na+ triggers the Macula Densa, which vasoconstricts the AA to prevent the loss of precious Na+. The GFR falls.

Why this matters?

It’s a vicious cycle, which makes the kidney really vulnerable during shock.

What parts of the nephron are most vulnerable?

Sections with lots of NaK Pumps: the PCT and the Thick Ascending Limb.

Nephrotoxic ATN is when the nephron is poisoned. Memorize this list of nephrotoxic agents: Aminoglycosides, Radiocontrast dye, Urate, Myoglobin, Heavy Metals and Ethylene Glycol. What parts of the nephron are most vulnerable? Nephrotoxins will damage the first cells they touch -- the PCT.

Explanation of Labwork in ATN

Plug formation → GFR is low → can’t filter BUN or Cr → Azotemia

Tubular epithelial cell death → Reabsorption of BUN is impossible → BUN / Cr ratio is low (less than 15)

Tubular epithelial cell death → K+ excretion is impossible → Hyperkalemia

Tubular epithelial cell death → Organic acid excretion is impossible → Anion Gap Metabolic Acidosis

Tubular epithelial cell death → Muddy brown or Granular epithelial casts (pathognomonic)

NaK Pump Polarity reversal → FENa is high (more than 2%)

Urine Output is variable. It’s low initially, then high during recovery.

ACUTE INTERSTITIAL NEPHRITIS

Intrinsic

I like to think of Acute Interstitial Nephritis (AIN) as an allergic drug reaction that only impacts the kidney’s connective tissue. It helps me to remember that it’s always triggered by a drug, that there’s eosinophilia and that AIN usually involves a rash. AIN is usually triggered by a drug -- the common culprits being Sulfa drugs (think TMP-SMX), Rifampin, NSAIDs, Diuretics (Furosemide & Thiazides) and Penicillins (especially Methicillin). Discontinuing the offending drug will cure the condition. About 10% of AIN cases are caused by something other than medications: Sarcoidosis, Lupus, Sjogrens or an infection (many different agents), but that’s low yield. AIN causes AKI. It presents similarly to ATN (Oliguria and Azotemia), plus a fever and a rash. Overall, AIN has lots of inflammation going on. WBCs will spill into the urine. That includes Eosinophils (after all, it’s an allergic drug reaction). WBC Casts are sometimes seen in AIN. WBC Casts are also seen in Pyelonephritis. But in AIN, there isn’t bacteriuria or dysuria. Inflammation-rich urine in the absence of an infection is called “sterile pyuria.”

Chronic Interstitial Nephritis (CIN) is seen with longstanding NSAID use -- this is concerning because millions of people use NSAIDs every day for chronic pain. Here’s the MOA. Mononuclear cells infiltrate the interstitium, and that causes fibrosis and atrophy of the tubules. The patient will be asymptomatic and have mild Azotemia (often found incidentally). Stopping the NSAIDs resolves the condition. This is pretty low yield.

AIN can progress to Renal Papillary Necrosis. The papillae have especially small arteries, making them vulnerable to ischemia. RPN produces gross hematuria (which is unusual in kidney problems), flank pain and sometimes a fever. The most common cause is NSAID use, but other potential causes are sickle cell disease, sickle cell trait, infection, inflammation or obstruction.

DRUGS VS. THE KIDNEY

NSAIDs are perhaps the most relevant nephrotoxic medication. They can hurt the kidneys in several different ways.

A lot of other drugs hurt the kidneys. Here’s a big list of ‘em

ATN - Acute Tubular Necrosis

AIN - Acute Interstitial Nephritis

MN - Membranous Nephropathy

Other Nephrotoxic Drugs: Methotrexate, Cyclosporin, Tacrolimus, Foscarnet, Cidofovir, Colchicine, Methoxyflurane

ASPIRIN OVERDOSE

Salicylate poisoning

Aspirin poisoning manifests with hyperventilation early on. After about 24 hours, they go into metabolic overdrive. Their blood becomes acidotic, they develop nausea, abdominal pain, tinnitus, fever and confusion. In severe cases, seizures and respiratory depression can lead to death. The treatment is urine alkalinization with Sodium Bicarb and, if necessary, dialysis.

RENAL TUBULAR DEFECTS

Highlighting normal nephron physiology

Fanconi Syndrome is when the proximal convoluted tubule breaks. The PCT reabsorbs a lot of wonderful molecules like glucose, amino acids, phosphate and bicarbonate. Without these building blocks, growth retardation and rickets will occur. Without bicarbonate, metabolic acidosis will occur (non-anion gap). Fanconi Syndrome has many unusual causes, including inherited mutations, heavy metal disorders (Wilson disease, lead, platinum drugs), sugar disorders (Glycogen storage disorders, Fructose intolerance) and amino acid disorders (Tyrosinemia).

Bartter Syndrome is when the thick ascending limb of the loop of Henle breaks. It’s like taking a loop diuretic. The thick ascending limb reabsorbs water, sodium, potassium and chloride. Bartter Syndrome results in hypokalemia plus a metabolic alkalosis (see metabolic alkalosis page). The customer barttered for a pair of loop earrings.

Gitelman Syndrome is when the distal convoluted tubule breaks. It’s like taking a thiazide diuretic. The DCT helps you reabsorb sodium, chloride and water, while getting rid of calcium. Gitelman leads to contraction alkalosis and hypercalcemia, but it is overall milder than Bartter and Fanconi.

Liddle Syndrome is when the principal cells of the collecting duct are overactivated when their sodium channels (ENaC) become invincible to degradation. It’s similar to hyperaldosteronism, except the serum levels of aldosterone are low. Aldosterone raises the blood pressure at the expense of losing potassium. It also creates a metabolic alkalosis. The treatment is aimed at blocking the overactive ENaC channels with Amiloride or Triamterene.

Syndrome of Apparent Mineralocorticoid Excess (SAME) is clinically similar to Liddle Syndrome; however, the culprit mineralocorticoid is not Aldosterone, but Cortisol. With Liddle Syndrome, the ENaC channels that are upregulated by Aldosterone were to blame. With SAME, the culprit is Cortisol. We have to take a step back for a moment to talk about Cortisol and Cortisone. These are both endogenous steroids. Cortisol has more mineralocorticoid properties than Cortisone does. Cortisol is normally transformed into Cortisone by the 11b-Hydroxysteroid DH enzyme. In SAME, that enzyme is defective. The defection either occurs because you inherit a mutation from your parents, or because the enzyme is disabled by licorice! This results in lots of Cortisol and little Cortisone. A bit confusing, I know. You can either treat with an ENaC blocker or with an exogenous steroid (to suppress production of Cortisol).

RENAL TUBULAR ACIDOSIS

Urinary NAGMA

The Renal Tubular Acidoses are a horribly complicated group of rare ion channel defects that occur in the nephron. They all cause a non-anion gap metabolic acidosis (NAGMA), but the anion gap in their urine is high. If you’re feeling masochistic, you can look up the different causes of RTA in FirstAid, but I consider it low yield.

Type 1 RTA occurs in the distal convoluted tubule (confusingly). The a-intercalated cells lose the ability to generate H+ and bicarbonate. The blood becomes acidic while the urine gets basic.

Type 2 RTA occurs in the proximal convoluted tubule. The PCT can’t reabsorb bicarb. Patients pee out all of their basic bicarbonate, leaving their blood more acidic. It’s less severe than type 1 because the downstream α-intercalated cells can still acidify the urine. Because of this watering-down effect, the urine anion gap is normal.

Type 4 RTA occurs when aldosterone is low. It’s not a true ion channelopathy. Without aldosterone, the principal cells are unable to make the compensatory acid NH3 (the reason for this is a bit complicated, so I’ll omit it). This is the only RTA where the serum potassium is high (because aldosterone is low).

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